Ultrasound to deliver medicine to ‘inoperable’ liver cancer tumours

Researchers at the University of Oxford have used focused ultrasound in a phase 1 clinical trial to selectively heat inoperable liver tumours and trigger the release of cancer drugs from thermosensitive liposomes.

The patients received a single intravenous dose of 50mg/m2 of doxorubicin, a chemotherapy drug, encapsulated within low-temperature-sensitive liposomes while under general anaesthesia. Using an approved ultrasound-guided focussed ultrasound device, at the Early Phase Clinical Trials Unit at the Churchill Hospital in Oxford, the target tumour was selectively heated to over 39.5° Celsius. The temperature of the target tumour was measured in two ways. In six out of 10 patients, a temporarily implanted probe was used, whilst in the remaining four patients non-invasive ultrasonic heating was carried out.

“Ultrasound to deliver medicine to ‘inoperable’ liver cancer tumours“

Professor Constanin Coussios, director of the Oxford Centre for Drug Delivery Devices, remarked that “Reaching therapeutic levels of cancer drugs within a tumour, while avoiding side effects for the rest of the body is a challenge for all cancer drugs, including small molecules, antibodies and viruses. Our study is the first to trial this new technique in humans, and finds that it is possible to safely trigger and target the delivery of chemotherapy deep within the body from outside the body using focussed ultrasound. Once inside the tumour, the drug is released from the carrier, supplying a higher dose of chemotherapy directly to the tumour, which may help to treat tumours more effectively for the same or a lower systemic dose of the drug.”

The amount of drug reaching the tumour passively, prior to focussed ultrasound exposure, was estimated to be below therapeutic levels. Across all patients chemotherapy concentrations within the liver tumour after the focussed ultrasound increased by an average of 3.7 times, and in seven of the trial patients the levels were between 2 and 10 times higher.

Lead author of the study, Dr Paul Lyon, said “Only low levels of chemotherapy entered the tumour passively. The combined thermal and mechanical effects of ultrasound not only significantly enhanced the amount of doxorubicin that enters the tumour, but also greatly improved its distribution, enabling increased intercalation of the drug with the DNA of cancer cells. A key finding of the trial is that the tumour response to the same drug was different in regions treated with ultrasound compared to those treated without, including in tumours that do not conventionally respond to doxorubicin,” added Prof Mark Middleton, principal investigator of the study. “The ability of ultrasound to increase the dose and distribution of drug within those regions raises the possibility of eliciting a response in several difficult-to-treat solid tumours. This opens the way not only to making more of current drugs but also targeting new agents where they need to be most effective. We can now begin to realise the promise of precision cancer medicine.”

The study demonstrated that in most patients the ultrasound technique is capable of increasing drug delivery to the tumour between two-fold and ten-fold while remaining safe and feasible.